ROMP copolymers for orthogonal click functionalizations

Article abstract of DOI:10.1021/ma301061z

The ring-opening metathesis polymerization using ruthenium carbene initiators developed by Grubbs et al. is one of the most functional group tolerant living polymerization methods known. One of the most used postpolymerization functionalization methods used today is the copper-catalyzed 1,3-dipolar cycloaddition between alkynes and organic azides. Organic azides are, however, not tolerated by ruthenium carbene initiators, and nonprotected alkynes have been shown to slow down the propagation reaction or react with the propagating species leading to broad molecular weight distributions. Here we report the copolymer synthesis of three orthogonally functionalizable monomers: one carrying an activated pentafluorophenyl ester, one a maleimide unit, and a third one a trialkylsilyl-protected alkyne. From these monomers, statistical terpolymers as well as diblock copolymers were synthesized with different molecular weights and monomer compositions or block ratios, respectively. Excellent control over molecular weight and molecular weight distribution could be achieved using Grubbs' first-generation ruthenium carbene initiator. Herein we present the synthesis and orthogonal triple postpolymerization functionalization of these copolymers.

Full text of DOI:10.1021/ma301061z

Article
pubs.acs.org/Macromolecules
ROMP Copolymers for Orthogonal Click Functionalizations
Mark Schaefer, Nils Hanik, and Andreas F. M. Kilbinger*
́
Department of Chemistry, University of Fribourg, Chemin du Musee 9, CH-1700 Fribourg, Switzerland
*
S Supporting Information
ABSTRACT: The ring-opening metathesis polymerization using ruthenium carbene initiators developed by Grubbs et al. is one
of the most functional group tolerant living polymerization methods known. One of the most used postpolymerization
functionalization methods used today is the copper-catalyzed 1,3-dipolar cycloaddition between alkynes and organic azides.
Organic azides are, however, not tolerated by ruthenium carbene initiators, and nonprotected alkynes have been shown to slow
down the propagation reaction or react with the propagating species leading to broad molecular weight distributions. Here we
report the copolymer synthesis of three orthogonally functionalizable monomers: one carrying an activated pentafluorophenyl
ester, one a maleimide unit, and a third one a trialkylsilyl-protected alkyne. From these monomers, statistical terpolymers as well
as diblock copolymers were synthesized with different molecular weights and monomer compositions or block ratios,
respectively. Excellent control over molecular weight and molecular weight distribution could be achieved using Grubbs’ first-
generation ruthenium carbene initiator. Herein we present the synthesis and orthogonal triple postpolymerization
functionalization of these copolymers.
1
. INTRODUCTION
carrying highly functional groups fulfilling the Sharpless criteria
of a click reaction (activated esters, alkynes, maleimides, etc.)
Since the term “click chemistry” was coined by Sharpless in
11−20
1
for postpolymerization modification is comparatively few.
2001, the interest in modular, widely applicable, and high
Our group has previously been reporting the synthesis of
yielding reactions has virtually exploded. In polymer chemistry
in particular, high yielding reactions have always been the
foundation of all step-growth processes and postpolymerization
modifications of polymer side- and end-groups. Focusing on
chemoselectivity and orthogonality, postpolymerization mod-
ifications offer a synthetic pathway leading to functional
polymers with defined molecular weight, composition, and
architecture. This method can therefore facilitate the establish-
ment of structure−property relationships in e.g. combinatorial
material discovery due to the synthesis of a broad variety of
functional polymers based on one single polymer precursor.
With the advancements of living radical polymerization
techniques, well-defined polymers capable of undergoing high
yielding postpolymerization functionalization have received
increased attention. Theato and Klok recently reviewed the
functional ROMP polymers in particular those with functional
21−27
end-groups
modification.
or end-groups capable of alkyne azide click
28
ROMP polymers carrying azide and alkyne moieties were
prepared by Kluger et al. as well as Weck et al. in a two-step
process from an imide or alkyl bromide functionalized
1
2,20
polymer.
In contrast, we utilized a complementary
approach starting from a trimethylsilyl-protected alkyne in
order to avoid side reactions of the intermediate alkyl bromide.
It was reported that the Grubbs’ first-generation ruthenium
29
initiator did not tolerate the alkyl azide side group in the
monomer repeat unit and propagation was slowed down
significantly, and the molecular weight distribution broadened
1
2,30,31
by an unprotected alkyne.
showed a synthetic approach to protect the alkyne moiety in a
norbornene derivative using Co (CO) . There the complexed
The group of Tew recently
2
areas of active ester-functionalized polymers and postpolyme-
3
,4
rization functionalization of polymers in general. The group
2
6
norbornene carrying alkyne could be polymerized in a ring-
of Binder reviewed the azide−alkyne click reaction in the
5,6
context of polymer and material science. In fact, most of the
examples reported on postpolymerization modifications were
Received: May 24, 2012
Revised: August 3, 2012
7
−10
prepared by living radical polymerizations,
whereas the
number of living ring-opening metathesis polymers (ROMP)
©
XXXX American Chemical Society
A
dx.doi.org/10.1021/ma301061z | Macromolecules XXXX, XXX, XXX−XXX

Macromolecules
Article
opening metathesis polymerization using Grubbs’ third-
excess of oxalyl chloride (1.2 equiv) and stirred at room temperature
for 1 h before removal of residual chlorination agent. After addition of
triethylamine (25 mL), pentafluorophenol (13.79 g, 74.9 mmol, 1
equiv) in triethylamine (5 mL) was added dropwise within 30 min.
After stirring for 3 h at room temperature the solvent was evaporated
and the product purified via column chromatography with chloroform
3
2
generation initiator. Krovi et al. could show that a
trimethylsilyl-protected alkyne connected to the norbornene
moiety via an oligoethylene glycol spacer could be polymerized
33
using Grubbs’ first-generation initiator. Because of presence
of a variety of different functional groups, we chose the more
stable Grubbs’ first-generation initiator in particular as its third
generation analogue led to very similar molecular weights and
polydispersities. Here we present the synthesis of statistical
terpolymers as well as diblock copolymers via living ROMP that
carry a combination of alkyne−azide click, activated ester−
amine click, and maleimide−thiol click functionalizable repeat
units for orthogonal postpolymerization derivatization.
1
as eluent. Yield: 29.52 g, 68.3 mmol, 91%. H NMR (400 MHz,
CDCl ), δ (ppm): 6.32−6.28 (m, 2H, CCH); 4.19−4.10 (m, 2H,
3
1
4
O−CH ); 3.27 (s, 1H, C CH); 3.20 (s, 1H, C CH); 2.97−2.94 (dd,
2
3
3
3
3
1H, J = 9.6 Hz, J = 1.7 Hz, C CH); 2.78−2.77 (d, 1H, J = 3.5 Hz,
1
2
2
2
C CH); 2.12−2.09 (d, 1H, J = 9.6 Hz, CH
-bridge); 1.58−1.56 (m,
2
1H, CH -bridge); 1.41−1.26 (m, 6H, hexyl-chain); 0.91−0.86 (m, 3H,
2
1
3
CH3). C NMR (100 MHz, CDCl ), δ (ppm): 173.68 (CO−OAl);
3
1
1
4
69.58 (CO−OAr); 142.92, 139.53, 137.91, 136.42 (Ar); 138.53,
2
37.44 (CC); 65.39 (O−CH ); 47.83 (C ); 47.35 (CH -bridge);
2
2
1
3
4
6.69 (C ); 46.59 (C ); 46.20 (C ); 31.38, 28.55, 25.49, 22.45 (CH -
2
1
9
2
. EXPERIMENTAL SECTION
chain); 13.93 (CH3). F NMR (377 MHz, CDCl ), δ (ppm):
3
(
−154.89)−(−155.01) (ortho C−F); (−160.69)−(−160.99) (para
C−F); (−165.07)−(−165.33) (meta C−F). FD-MS: 432.3, 433.3,
34.3 m/z (432.1 calcd).
.4. Synthesis of the Protected Alkyne Monomer. exo-
Norbornene-2,3-dicarboximide (3). exo-Carbic anhydride (15.03 g,
1.37 mmol, 1 equiv) and aqueous ammonia (25%) (100 mL) were
2
.1. Materials. Ammonium hydroxide solution, benzyl mercaptan,
benzylidene−bis(tricyclohexylphosphine)dichlororuthenium (Grubbs’
first-generation catalyst), chlorotriisopropylsilane, chlorotrimethylsi-
lane, 1-dodecylamine, ethyl vinyl ether, 1-hexanol, 1-hexylamine,
maleic anhydride, phosphorus pentoxide, piperonyl alcohol, propargyl
bromide solution, sodium L-ascorbate, sodium azide, tetrabromo-
methane, tetrabutylammonium fluoride solution (1 M in THF), p-
toluenesulfonyl chloride, 5-(trimethylsilyl)-4-pentyn-1-ol, and triphe-
nylphosphine were purchased from Sigma-Aldrich and used without
further purification. Acetic anhydride, n-butyllithium solution, oxalyl
chloride, pentafluorophenol, potassium carbonate, and copper(II)
sulfate hydrate were purchased from Acros, ABCR, Merck, or
Reactolab and used without further purification. Triethylamine
4
2
9
combined in a round-bottom flask equipped with reflux condenser and
drying tube before heating to reflux for 48 h. Crystallization occurred
overnight, and the colorless powder was filtered and washed with
hexane. Yield: 11.52 g, 70.60 mmol, 77%. 1H NMR (300 MHz,
CDCl ), δ (ppm): 8.66 (brs, 1H, NH); 6.28 (s, 2H, CCH); 3.29 (s,
3
2
2
H, =CH−CH); 2.73 (s, 2H, CO−CH); 1.59−1.56 (d, 1H, J = 9.99
2
13
Hz, CH -bridge); 1.47−1.44 (d, 1H, J = 9.99 Hz, CH -bridge).
C
2
2
NMR (75 MHz, CDCl ), δ (ppm): 178.42 (CO); 137.72 (CC);
(
Acros) and ethylenediamine (Sigma) were freshly distilled before
3
4
1
9.14 (CO-CH); 45.10 (=CH−CH); 42.88 (CH -bridge). ESI-MS:
usage, and endo-carbic anhydride (Acros) was heated to 180 °C for 2 h
and recrystallized from benzene to obtain pure exo-carbic anhydride.
2
86.0, 187.0, 188.0 m/z (163.1 calcd + sodium).
exo-N-[5-(Trimethylsilyl)pent-4-yn-1-yl]-5-norborene-2,3-dicar-
2.2. Characterization. Standard nuclear magnetic resonance
boximide (5). Anhydrous potassium carbonate (1.09 g, 7.9 mmol, 1.3
equiv), compound 3 (1.09 g, 6.7 mmol, 1.1 equiv), and dry acetone
(15 mL) were combined in a Schlenk flask and stirred for 10 min at 55
°C before compound 4 (1.84 g, 6.1 mmol, 1.0 equiv) dissolved in dry
acetone (10 mL) was added dropwise via a syringe. After 48 h at 55
spectra as well as two-dimensional spectra were recorded at 300
1
13
19
MHz ( H NMR)/75 MHz ( C NMR)/282 MHz ( F NMR) on a
1
13
Bruker Avance III 300 or at 400 MHz ( H NMR)/100 MHz ( C
19
NMR)/377 MHz ( F NMR) on a Bruker DPX 400 spectrometer. All
NMR signals were referenced internally to residual solvent signals or
trifluoroacetic acid in the case of fluorine NMR. Relative molecular
weights and molecular weight distributions were measured by gel
permeation chromatography (GPC) equipped with a Viscotek
GPCmax VE2001 GPC Solvent/Sample Module, a Viscotek UV-
Detector 2600, a Viscotek VE3580 RI-Detector, and two Viscotek
°
C, the mixture was filtered and the organic solvent removed. The
crude product was purified via column chromatography with
1
dichloromethane as eluent. Yield: 1.52 g, 5.0 mmol, 83%. H NMR
(
3
3
300 MHz, CDCl3), δ (ppm): 6.28 (t, 2H, J = 1.70 Hz, CCH);
3
.57−3.52 (m, 2H, N−CH ); 3.27 (t, J = 1.70 Hz, 2H, =CH−CH);
2
3
3
3
7
2.67 (d, J = 1.32 Hz, 2H, CO−CH); 2.22−2.27 (t, 2H, J = 1.80 Hz,
T6000 M columns (7.8 × 300 mm, 10 −10 Da each). All
measurements were carried out at room temperature using THF as
the eluent with a flow rate of 1 mL/min. The system was calibrated
3
≡
C−CH ); 1.83−1.74 (q, 2H, J = 7.36 Hz, N−CH −CH ); 1.54−
2 3
2
2
2
1
.49 (dt, 1H, J = 9.82 Hz, J = 1.51 Hz, CH -bridge); 1.29−1.26 (d,
2
2
1
3
3
6
1H, J = 10.01 Hz, CH -bridge); 0.14 (s, 9H, CH ). C NMR (75
with polystyrene standards in a range from 10 to 3 × 10 Da. Field
desorption mass spectra were measured on a Finnigan MAT 95 and
electrospray ionization mass spectra on a Bruker Esquire HCT.
2
3
MHz, CDCl3), δ (ppm): 177.86 (CO); 137.77 (CC); 105.40
CH −C≡); 85.41 (Si−C≡); 47.77 (CO−CH); 45.11 (=CH−CH);
(
2
4
2.77 (CH -bridge); 37.86 (N−CH ); 26.71 (N−CH −CH ); 17.71
2
.3. Synthesis of the Reactive Ester-Containing Monomer.
2
2
2
2
(
≡C−CH ); 0.03 (CH ). ESI-MS: 324.1, 325.1 m/z (301.1 calcd +
exo-3-[(Hexyloxy)carbonyl]norbornene-2-carboxylic Acid (1). To a
solution of exo-carbic anhydride (15.0 g, 91.4 mmol, 1 equiv) in
dichloromethane (300 mL) and a catalytic amount of triethylamine, 1-
hexanol (9.34 g, 91.4 mmol, 1 equiv) was added dropwise at room
temperature before heating to reflux overnight. After removal of the
2
3
sodium).
2.5. Synthesis of the Maleimide-Containing Monomer. exo-
N-(2-Aminoethyl)-5-norbornene-2,3-dicarboximide (6). To freshly
distilled ethylenediamine (50 mL, 0.75 mol, 8.2 equiv) a solution of
exo-carbic anhydride (15.0 g, 91.4 mmol, 1 equiv) in toluene (300 mL)
was added dropwise over 1.5 h under mechanical stirring. The mixture
was held under Dean−Stark conditions overnight before the solvent as
well as residual ethylenediamine were removed via distillation.
Purification was achieved by column chromatography with chloro-
form: methanol (1%→10%) as eluent. Yield: 14.67 g, 71.1 mmol, 78%.
solvent the product was recrystallized from petroleum ether. Yield:
1
2
0.17 g, 75.7 mmol, 83%. H NMR (400 MHz, CDCl ), δ (ppm): 6.23
3
(
s, 2H, CCH); 4.11−3.98 (m, 2H, O−CH ); 3.12 (s, 2H, =CH−
2
2
CH); 2.65 (s, 2H, CO−CH); 2.13−2.11 (d, 1H, J = 9.6 Hz, CH -
2
3
bridge); 1.64−1.57 (quint, 2H, J = 7.0 Hz, O−CH −CH ); 1.51−
2
2
2
1
.49 (d, 1H, J = 9.6 Hz, CH -bridge); 1.37−1.24 (m, 6H, hexyl-
2
1
3
13
H NMR (300 MHz, CDCl ), δ (ppm): 6.23 (t, 2H, J = 1.70 Hz, C
chain); 0.91−0.88 (m, 3H, CH ). C NMR (100 MHz, CDCl ), δ
3
3
3
3
3
(
(
(
1
ppm): 179.99 (COOH); 173.39 (COO−C); 138.10 and 137.79
CH); 3.48 (t, 2H, J = 6.42 Hz, CO−N−CH
2
); 3.21 (t, 2H, J = 1.70
3
4
2
3
3
CC); 65.01 (O−CH ); 47.56 (C ); 47.30 (C ); 45.72 (C ); 45.45
Hz, =CH−CH); 2.83 (t, 2H, J = 6.42 Hz, CH
2
−NH
2
); 2.64 (d, 2H, J
2
1
2
3
C ); 45.34 (CH -bridge); 31.41, 28.39, 25.57, 22.49 (CH -chain);
= 1.32 Hz, CO−CH); 1.47−1.43 (dt, 1H, J = 9.82 Hz, J = 1.32 Hz,
2
2
2
13
3.99 (CH ). FD-MS: 265.4, 266.4, 267.4, 268.4, 269.4 m/z (266.2
CH
2
-bridge); 1.31−1.28 (d, 1H, J = 9.82 Hz, CH
2
-bridge). C NMR
3
calcd).
exo-2-Hexyl-3-(pentafluorophenyl)norbornene-2,3-dicarboxylate
2). Compound 1 (19.95 g, 74.9 mmol, 1 equiv) was dissolved in an
(75 MHz, CDCl
(CO−CH); 45.02 (=CH−CH); 42.65 (CH
CH ); 39.77 (CH −NH ).
3
), δ (ppm): 178.15 (CO); 137.63 (CC); 47.68
-bridge); 41.28 (CO−N−
2
(
2
2
2
B
dx.doi.org/10.1021/ma301061z | Macromolecules XXXX, XXX, XXX−XXX

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Scheme 1. Synthesis of “Clickable” ROMP Monomers That Can Be Functionalized Independently of Each Other
1
exo-N-[2-(1H-Pyrrole-2,5-dione)ethyl]-5-norbornene-2,3-dicar-
boximide (7). Compound 6 (10.66 g, 43.1 mmol, 1 equiv) and maleic
anhydride (5.07 g, 51.7 mmol, 1.2 equiv) were dissolved in DMF (12.8
mL) and cooled to 0 °C. A solution of phosphorus pentoxide (1.76 g,
was inverted once, and H as well as 19F NMR spectra were recorded
every 5 min for 1 h.
2.7. Copolymerization and Functionalization. General
Procedure for the Synthesis of Statistical Copolymers. A sealed
Schlenk-flask containing compounds 2, 5 and 7 (Scheme 1) was
evacuated and charged with argon gas repeatedly before degassed
dichloromethane (ca. 5 mL/g of monomer) was added via syringe.
The polymerization was initiated by quickly adding a solution of the
appropriate amount of Grubbs’ first generation catalyst in degassed
dichloromethane (ca. 1 mL per 100 mg). The reaction times depended
on the desired molecular weight of the individual copolymers. Upon
complete monomer conversion the polymerization was terminated
with ethyl vinyl ether (1 mL) before the polymer was precipitated in
ice-cold methanol and dried in a vacuum oven yielding 80−90% of a
brownish solid. Yield: 222 mg, 83%
General Procedure for the Synthesis of Block Copolymers. A
sealed Schlenk flask containing compound 2 (Scheme 1) was
evacuated and charged with argon gas repeatedly before degassed
dichloromethane (ca. 5 mL per gram of monomer) was added via
syringe. The polymerization was initiated by quickly adding a solution
of the appropriate amount of Grubbs’ first-generation catalyst in
degassed dichloromethane (ca. 1 mL per 100 mg). The reaction times
depended on the desired molecular weight of the individual block (60
4
.6 mmol, 0.1 equiv) in DMF (6.4 mL) and sulfuric acid (1.01 g) was
added dropwise, and the ice bath was removed upon complete
addition. The solution was heated to 70 °C for 2 h, poured on iced
water, and extracted with chloroform. Upon removal of the solvent the
crude product was dissolved in acetic anhydride (50 mL), sodium
acetate was added, and the solution was heated to 100 °C for 2 h.
Upon extraction with chloroform the product was purified by column
chromatography with chloroform:methanol (5%) as eluent. Yield:
1
1
(
1.28 g, 39.4 mmol, 91%. H NMR (300 MHz, CDCl ), δ (ppm): 6.68
3
3
s, 2H, CO−CH=); 6.25 (t, 2H, J = 1.70 Hz, =CH−CH⟨); 3.75−3.67
3
(
m, 4H, N−CH ); 3.22 (t, 2H, J = 1.70 Hz, =CH−CH); 2.65 (d, 2H,
2
3
2
3
J = 1.32 Hz, CO−CH⟨); 1.52−1.51 (dt, 1H, J = 10.01 Hz, J = 1.51
2
13
Hz, CH -bridge); 1.26−1.23 (d, 1H, J = 9.82 Hz, CH -bridge).
C
2
2
NMR (75 MHz, CDCl ), δ (ppm): 177.97 (⟩CH−CO); 170.57
3
(
(
=CH−CO); 137.74 (=CH−CH⟨); 134.16 (=CH−CO); 47.89
CO−CH); 44.92 (=CH−CH); 42.90 (CH -bridge); 37.30 (⟩CH−
2
CO−N−CH ); 36.17 (CH −N−CO−CH=). ESI-MS: 309.1, 310.1
2
2
m/z (286.1 calcd + sodium).
.6. NMR Studies for Orthogonal Functionalization. Func-
tionalization with Mercaptans. A mixture of compounds 2 (12 mg,
.03 mmol, 1 equiv) and 7 (8 mg, 0.03 mmol, 1 equiv) in 0.6 mL of
2
−1
−1
min for 5000 g mol , 90 min for 10 000 g mol , and 120 min for 20
−
1
0
000 g mol , all at room temperature). Upon complete monomer
conversion a solution of compound SI2 in dichloromethane (ca. 2 mL
per gram of monomer) was added via syringe, and the mixture was
stirred until no residual monomer was left (determined via GPC). The
polymerization was terminated with ethyl vinyl ether (1 mL) before
the product was either precipitated in ice-cold methanol and/or
purified via column chromatography with dichloromethane as eluent.
The block copolymer was dried in a vacuum oven yielding 70−90% of
a brownish solid. Yield: SI3a 203 mg, 73% (after column
chromatography and precipitation); SI3b 371 mg, 86% (after column
chromatography and precipitation)
Functionalization with Benzyl Mercaptan. A sealed Schlenk flask
containing the precursor polymer was evacuated and charged with
argon gas repeatedly before dissolving in degassed dichloromethane
(ca. 3 mL per 100 mg of polymer). A solution of benzyl mercaptan
(150 mg per 100 mg of polymer) and freshly distilled triethylamine (1
mL per 150 mg of benzyl mercaptan) was added via syringe, and the
1
CDCl was filled into a NMR tube, and H NMR has been measured.
3
Benzyl mercaptan (7 mg, 0.06 mmol, 2 equiv) was added, the NMR
1
19
tube inverted once, and H as well as F NMR spectra recorded every
min for 1 h. The same procedure was performed for the subsequent
5
addition of triethylamine (10 mg, 0.10 mmol, 3.3 equiv).
Functionalization with Amines. A mixture of compounds 2 (10
mg, 0.02 mmol, 1 equiv) and 7 (7 mg, 0.02 mmol, 1.1 equiv) in 0.6 mL
of CDCl3 was filled into a NMR tube, and 1H NMR has been
measured. Benzylamine (7 mg, 0.06 mmol, 3 equiv) was added, the
1
19
NMR tube inverted once, and H as well as F NMR spectra were
recorded every 5 min for 1 h.
Alkyne Deprotection with TBAF. A mixture of compounds 2 (12
mg, 0.03 mmol, 0.9 equiv), 5 (9 mg, 0.03 mmol, 1 equiv), and 7 (8 mg,
0
.03 mmol, 0.9 equiv) in 0.6 mL of THF-d was filled into a NMR
8
1
19
tube, and H as well as F NMR has been measured. TBAF ([1 M] in
THF-d , 0.05 mL, 0.05 mmol, 1.7 equiv) was added, the NMR tube
8
C
dx.doi.org/10.1021/ma301061z | Macromolecules XXXX, XXX, XXX−XXX

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Scheme 2. Synthesis of Piperonyl Azide for the Attachment to Polymeric Alkynes via CuAAC
Scheme 3. Synthesis of Alkyne-Containing Monomers with a Short Spacer SI2a,b
mixture was stirred for 3 h at room temperature before precipitating in
a 10-fold excess of ice-cold methanol. Yield: 127 mg, 91%.
Functionalization with Alkylamines. A sealed Schlenk flask
containing the precursor polymer was evacuated and charged with
argon gas repeatedly before dissolving in degassed dichloromethane
The reaction of exo-carbic anhydride with 1-hexanol (1) was
followed by the in situ synthesis of the carboxylic acid chloride
using oxalyl chloride and its subsequent treatment with
pentafluorophenol yielding compound 2 (91%). During the
formation of this amine-selective ester a side reaction occurred,
converting the before pure exo compound 1 into an endo/exo
(
ca. 3 mL per 100 mg of polymer). A solution of the corresponding n-
alkylamine (150 mg per 100 mg of polymer) in freshly distilled
triethylamine (1 mL per 150 mg of alkylamine) was added via syringe,
and the mixture was stirred overnight at room temperature before
precipitating in a 10-fold excess of ice-cold methanol. The yield,
depending on the polymer, was around 90%. Yield: 12 84 mg, 88%;
SI4a 92 mg, 90%; SI4b 134 mg, 87%.
1
mixture of 2 via a ketene intermediate as shown by H NMR
spectroscopy (see Supporting Information, Figure SI1). Field
desorption mass spectrometry confirmed the formation of the
desired product. The reactive pentafluorophenyl ester can easily
and selectively be reacted with alkylamines. Functional groups
such as dyes, binding sites for biomolecules, and nanoparticles
or other functional groups can thus be introduced readily via
this type of high yielding “click” reaction.
Functionalization via CuAAC. (a) Deprotection of the Alkyne.
Procedure 1: The statistical copolymer was dissolved in tetrahydrofur-
an containing 5% water (5 mL per 100 mg) under an inert
atmosphere, and tetrabutylammonium fluoride solution (1 M in
THF, 0.5 mL per 100 mg polymer) was added. The mixture was
stirred for 24 h at room temperature, and the polymer precipitated in a
The trimethylsilyl-protected alkyne 5 was synthesized via the
34
corresponding tosylate 4 (Scheme 1), whereas alkynes SI2a,b
1
0-fold excess of ice-cold methanol. Yield: 13 69 mg, 92%.
Procedure 2: The block copolymer was dissolved in a mixture of
(Scheme 3) were synthesized according to reported syntheses
3
5
of their non-silyl-protected analogues. First, propargyl
bromide was deprotonated with n-butyllithium before reacting
it with the corresponding chlorotrialkylsilane (a: trimethylsilyl
chloride (61%); b: triisopropylsilyl chloride (59%)). Norbor-
neneimide 3 was prepared and N-alkylated using 4 and SI1a,b
to give monomers 5 (83%) and SI2a,b (84% and 75%)
chloroform and methanol (10:1, 15 mL per 200 mg of polymer) under
an inert atmosphere, anhydrous potassium carbonate (same amount as
polymer) was added, and the mixture was stirred for 72 h at 50 °C.
After filtration and removal of the solvents, the polymer was
redissolved in a small amount of dichloromethane and precipitated
in a 10-fold excess of ice-cold methanol. Yield: SI5a 45 mg, 56% (after
reprecipitating 3 times); SI5b 66 mg, 47% (after reprecipitating 3
times).
36
according to a literature procedure. All monomers were fully
1
13
characterized via H and C NMR spectroscopy as well as
electrospray ionization mass spectrometry.
(b) CuAAC Reaction: The cycloaddition was carried out in a
biphasic mixture of dichloromethane and water (1:1). The polymer
and compound 9 (1.25 equiv with respect to the content of alkyne
included in the polymer) were dissolved in the organic solvent (2 mL
per 50 mg of piperonyl azide), whereas copper(II) sulfate hydrate
In order to have a substrate to evaluate the alkyne−azide
click reaction within the polymers we prepared from monomers
5
and SI2a,b, we synthesized azide 9 (Scheme 2) (78%
37
overall). Piperonyl azide was synthesized in a two-step
reaction starting from 5-(methanol)-1,3-benzodioxole (Scheme
(
0.04 equiv) and sodium L-ascorbate (0.22 equiv) were dissolved in
the same amount of water. The combined solutions were stirred at
room temperature overnight before the phases were separated, and the
aqueous phase was extracted twice with dichloromethane. Precip-
itation in a 10-fold excess of ice-cold methanol or column
chromatography with dichloromethane as eluent was utilized to
separate the polymer from residual azide. Yield: 14 50 mg, 83% (after
precipitation); SI6a 20 mg, 33% (after column chromatography and
precipitation); SI6b 60 mg, 75% (after precipitation).
2
, left) via Appel bromination using tetrabromomethane and
triphenylphosphine (8) (89%), followed by nucleophilic
substitution with sodium azide to give 9 (88%).
The conversion from 5-(methanol)-1,3-benzodioxole via the
1
intermediate 8 to the final product 9 could be followed by H
NMR spectroscopy (see Supporting Information, Figure SI3)
where the chemical shift of the benzylic CH protons changed
2
from a doublet at 4.58−4.56 ppm (5-(methanol)-1,3-
benzodioxole) via a singlet at 4.47 ppm (8) to a singlet at
4.24 ppm (9).
First attempts of combining ring-opening metathesis
polymerization and the well-established copper-catalyzed
3
. RESULTS AND DISCUSSION
A norbornene carrying a hexyl ester in addition to an activated
pentafluorophenyl ester (2, Scheme 1) could easily be
synthesized in high yield (76% overall) in a two-step reaction.
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Figure 1. Deprotection of monomer SI2 with TBAF in THF (red, only alkyne at 2.19 ppm) and DMF (blue, allene at 5.40 and 6.63 ppm as well as
alkyne at 2.19 ppm). Blue spectrum with offset of 0.1 ppm.
alkyne−azide cycloaddition were studied on two easy-to-
synthesize monomers SI2a,b.
tetrahydrofuran and on the other hand to prevent allene
formation due to spatial separation of the highly electronegative
nitrogen atom and the alkyne moiety. To verify this
assumption, monomer 5 was deprotected with tetrabutylam-
monium fluoride in the same solvents used before and only
formation of the expected alkyne was observed. Having this
new monomer at hand, the same studies were carried out
utilizing the corresponding polymer leading to a fully
deprotected and organo-soluble product.
In order to evaluate the chemical stability of each
functionalizable group contained in monomers 2, 5, and 7
toward the reaction conditions of the three different
postpolymerization treatments, trial experiments were carried
out in separate NMR tubes to follow potential product
degradation or formation of byproducts.
First, the potential Michael addition of amines to the
maleimide function was investigated, and as can be seen in
Figure 3, the integral corresponding to its double bond
decreased with time (Scheme 4, A, red). This indicated slow
addition and hence chemical instability toward further
nucleophiles present in the reaction mixture. Upon addition
of tetrabutylammonium fluoride to a separate mixture of
monomers 2, 5, and 7 the spectrum did not indicate any sign of
reaction or degradation of the maleimide function (Scheme 4,
B, product not shown because unreactive toward TBAF).
Second, the stability of the activated ester was investigated by
exposing it to a mercaptan or to tetrabutylammonium fluoride
The resulting homo- and block copolymers indicated high
molecular weight polymers and low polydispersities, but
nevertheless, during the deprotection step, the homopolymers
became insoluble in various solvents such as chloroform,
tetrahydrofuran, methanol, and dimethyl sulfoxide. Independ-
ent of the deprotection conditions, TBAF in tetrahydrofuran or
potassium carbonate in methanol/chloroform, gelation oc-
curred, and the resulting product could not be analyzed further.
To shed light on the occurring side reaction, both monomers
were exposed to tetrabutylammonium fluoride in tetrahydro-
furan as well as dimethylformamide. Figure 1 shows that during
this treatment the protecting group was cleaved off
quantitatively in THF (red, with alkyne at 2.19 ppm), whereas
in DMF a mixture of the desired alkyne and the corresponding
allene was formed (blue, with alkyne at 2.19 ppm and allene at
5.40 and 6.63 ppm). This led us to the conclusion that the
precursor polymer got insoluble in THF upon formation of a
large number of terminal alkynes and that the allenes formed
under the same conditions in DMF, which led to cross-linking
of the polymer, also rendering it insoluble.
To overcome this limitation, a modified monomer (5) was
synthesized, bearing a longer spacer between the norbornene
and the alkyne moiety. The larger number of CH units was on
2
one hand introduced to increase the flexibility of the side chain
and hence the solubility of the resulting polymer in
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Figure 2. Deprotection of monomer 5 with TBAF in THF (red) and DMF (blue), both leading to pure alkyne at 1.97 ppm and absence of
corresponding allene. Blue spectrum with offset of 0.1 ppm.
1
Figure 3. H NMR spectra of a mixture of compounds 2, 5, and 7 before (blue) and 120 min after addition of benzylamine (red). Decreasing signal
intensity corresponding to the maleimide double bond at 6.68 ppm. Blue spectrum with offset of 0.1 ppm.
(
Figure 4). In the fluorine NMR spectra it can easily be seen
pentafluorophenol ester remains intact whereas degradation
occurs via addition of TBAF (red), and the free alcohol is set
that upon addition of benzyl mercaptan (green) the
F
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a
Scheme 4. Summary of Products (Green) and Byproducts (Red) Occurring during Postpolymerization Treatment
a
Monomers that were unreactive under the respective conditions are not shown on the product side of the chemical equations.
Figure 4. 19F NMR spectra of a mixture of compounds 2, 5, and 7 (blue), 120 min after addition of benzyl mercaptan/triethylamine (green), 14 h
after addition of TBAF (red), and 60 min after the addition of benzylamine (pink). Spectra without offset in the x-direction.
free if it is exposed to an amine (pink). Additionally, the
deprotection of the alkyne was performed utilizing potassium
carbonate which also lead to degradation of the activated ester
According to these results, a procedure to orthogonally
functionalize the precursor polymers could be established. First
it needs to be treated with a mercaptan to prevent Michael
addition of the amine to the maleimide function, followed by
(Figure SI12).
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Scheme 5. Synthetic Scheme Visualizing Statistical Copolymerization Leading to Multifunctional Precursor Polymers and Their
Orthogonal “Triple-Click” Reaction
1
Figure 5. H NMR spectrum of precursor polymer 10. No signals for potential enyne-metathesis products can be observed.
H
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addition of an amine that selectively reacts with the activated
ester. Finally, the alkyne deprotection can be carried out with
tetrabutylammonium fluoride in order to rule out degradation
of the pentafluorophenol ester under these reaction conditions.
Copper-catalyzed azide−alkyne cycloaddition between the
polymeric alkyne and compound 9 led to the fully function-
alized polymer 14.
Comparing the integral of the terminal methyl group (Figure 5,
a) at 0.87 ppm versus the integral of the maleimide double
bond (Figure 5, b) at 6.73 ppm and the TMS-protecting group
(Figure 5, c) at 0.14 ppm allowed us to calculate the content of
the three functional monomers (2 vs 5 vs 7). For polymer 10 a
ratio of m:n:o = 9.9:5.1:10.0 was found, which agreed well with
the aimed at values. Furthermore, it could be shown that
introducing a covalently bound protecting group renders the
alkyne sterically hindered and prevents enyne metathesis and
the formation of previously proposed resting states that slow
down propagation. Indicators for the absence of such side
reactions are the narrow molecular weight distribution (lack of
cross-linking) and the formation of the target molecular weight
as shown in Table 1.
With monomers 2, 5, and 7 in hand, we carried out a
statistical copolymerization using Grubbs’ first-generation
ruthenium carbene initiator (benzylidene−bis-
12
(
tricyclohexylphosphine)dichlororuthenium) according to
Scheme 5. Polymer samples were taken every 30 min in
order to confirm complete monomer conversion. The synthesis
of terpolymers gave good control over molecular weight
according to the chosen monomer/catalyst ratio based on the
living character of this polymerization technique. Polymer 10
with the intended composition m:n:o = 10:5:10 (see Scheme 5)
According to the procedure described above, the first click-
functionalization needs to be the Michael addition of benzyl
mercaptan, as a model compound, to the maleimide double
1
1
was synthesized and analyzed by H NMR spectroscopy
bond. In the H NMR spectrum, the aromatic protons can be
(
Figure 5) as well as gel permeation chromatography (Table 1).
integrated with respect to the terminal methyl group and the
alkyne-protecting group in order to calculate the degree of
functionalization. The composition of polymer 11 (Scheme 5)
was found to be m:n:o = 9.6:4.9:10.5, which in combination
with the disappearance of the peak corresponding to the
maleimide double bond at 6.73 ppm suggested complete
conversion of this click reaction. Subsequently, the function-
alization of the amine selective ester was performed utilizing n-
hexylamine, which also only served as a model reagent. This
resulted in the formation of polymer 12. In future investigations
this model amine could be substituted for a broad variety of
functional moieties bearing amino groups. The advantage of
this primary n-alkylamine is the fact that the terminal methyl
groups can easily be integrated and used to determine the
degree of functionalization as already described above. Here,
Table 1. Results of GPC Traces for Precursor Polymer 10
and Intermediates 11, 12, and 13 as Well as “Triple-Clicked”
Polymer 14
calculated
RI detector
Mn
Mn
Mw
elution time at peak
maximum [min]
sample [g/mol] [g/mol] [g/mol] PDI
1
1
1
1
1
0
1
2
3
4
8800
9400
8600
7900
9700
9700
9800
14 400
13 800
13 700
16 200
15 100
1.48
1.38
1.29
1.47
1.41
22.46
22.42
22.29
22.34
22.46
10 600
11 100
10 800
Figure 6. 19F NMR spectra of nonfunctionalized polymer 10 (blue) and functionalized polymer 12 (red). Complete conversion indicated by
disappearance of peaks a, b, and c.
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1
Figure 7. H NMR spectrum of polymer 13 showing complete liberation of the terminal alkyne by vanishing signal of the TMS protecting group at
0
.14 ppm as well as appearance of the terminal methyne b at 1.98 ppm.
1
Figure 8. H NMR spectra before and after the third click reaction (CuAAC). Occurrence of multiple signals corresponding to the protected
catechol but the triazole proton overlaps with these of the aromatic mercaptan.
J
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these calculations showed the following composition for
tion conditions used in order to elaborate a procedure leading
to an orthogonal triple-functionalization of a precursor
polymer. The maleimide functions could be reacted quantita-
tively with a model mercaptan and the active esters (PFP-
esters) with a model primary amine. Following the silyl
deprotection of the polymeric alkyne, a Cu-catalyzed alkyne−
azide click reaction could be carried out in high yields using a
model azide reagent. Protecting the reactive and strongly
coordinating alkynes with silyl protective groups yields
monomer structures that can easily be polymerized using
commercial ruthenium carbene initiators. In combination with
the high functional group tolerance of the olefin metathesis
reaction, we believe that the ROMP process has great potential
for the synthesis of highly reactive postpolymerizable
copolymers.
polymer 12 m:n:o = 9.8:4.7:10.5. Complete conversion could
1
9
also be proven in the F NMR spectrum due to complete
disappearance of the signals corresponding to the pentafluor-
ophenol ester (Figure 6).
For the alkyne to be suitable for CuAAC (copper-catalyzed
azide−alkyne cycloaddition), the silyl protective group had to
be cleaved quantitatively in order to ensure complete
conversion to the corresponding triazole. Utilizing the newly
synthesized alkyne-containing monomer 5 (Scheme 1), stand-
ard deprotecting conditions using a tetrabutylammonium
fluoride (TBAF) solution in THF led to quantitative cleavage
of the TMS protective groups under mild conditions whereas
polymers containing monomers SI2a,b needed to be exposed
to potassium carbonate in methanol for 72 h at 50 °C. The
quantitative removal of the trialkylsilyl group can be shown by
1
H NMR (Figure 7), but due to the peak overlap of the
ASSOCIATED CONTENT
Supporting Information
Synthetic procedure of compounds SI1a,b and SI2a,b as well as
■
terminal methyne proton at 1.98 ppm with signals of the
polymer backbone, it could not be integrated properly to
estimate the degree of functionalization.
S
*
8
and 9; NMR spectra of monomers 2, 5, and 7 as well as
Cu-catalyzed reaction of the terminal alkynes in polymer 13
with compound 9 (Scheme 2) yielded the corresponding 1,2,3-
triazoles. The copper(I) species were synthesized in situ by
reduction of catalytic amounts of copper(II) sulfate with an
excess of sodium L-ascorbate. The formation of the triazole can
additional NMR analysis of various intermediates; synthetic
scheme of block copolymer synthesis and postpolymerization
functionalization including NMR analysis as well as corre-
sponding GPC traces. This material is available free of charge
via the Internet at http://pubs.acs.org.
1
clearly be shown by investigating the H NMR spectra of the
final, fully functionalized polymer due to the occurrence of the
aromatic (Figure 8, a) and benzylic (Figure 8, c) protons as
well as the protons corresponding to the acetal (Figure 8, b).
Because of overlap of the triazole proton and the aromatic
protons of the benzyl mercaptan, the aromatic signal of the
former azide (Figure 8,a) will be used to estimate the degree of
functionalization m:n:o = 10.0:4.9:10.1.
AUTHOR INFORMATION
Corresponding Author
E-mail andreas.kilbinger@unifr.ch; Tel +41 (0)26 300 8713;
Fax +41 (0)26 300 9738.
■
*
Notes
The authors declare no competing financial interest.
According to the corresponding GPC traces (data in Table
), the addition of a mercaptan as well as the substitution
ACKNOWLEDGMENTS
1
■
reaction by an amine led to an increase of molecular weight.
For the latter this is believed to be due to the formation of a
strongly solvated amide, hence increasing the hydrodynamic
volume of polymer 12. The same effect occurred after the
alkyne-deprotection step where the nonpolar trimethylsilyl
group was cleaved off, revealing a C−H acidic alkyne. Also
contrary to our expectations, the apparent molecular weight of
polymer 14 was smaller after the functionalization. This
collapse is believed to be caused by aromatic interactions
between the side chains and due to poorer solvation of the
protected aromatic catechol groups leading to a decrease in
hydrodynamic volume.
The azide (9) used in this investigation served as a model
organic azide and can readily be replaced by other functional
organic azides. However, cleavage of the acetal protective group
contained in 9 can lead to a catechol group, which will be
exploited in the binding to metal oxide surfaces or nano-
particles. This is currently under investigation in our group.
This research project is funded by the Swiss National Science
Foundation (SNF). The authors thank Christof Storz for
valuable discussions regarding the synthesis of piperonyl azide 9
and its polymer analogous click reaction.
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